Severe PAH is the marked elevation of precapillary resistance in the pulmonary circulation which occurs sporadically and in families as an idiopathic form. It is also observed in association with diseases such as chronic venous thromboembolism, scleroderma, HIV infection, and cirrhosis (Fishman, “Etiology and Pathogenesis of Primary Pulmonary Hypertension: A Perspective,” Chest 114(3 Suppl):242S-247S (1998); Farber et al., “Pulmonary Arterial Hypertension,” New Engl. J. Med. 351(16):1655-65 (2004)). PAH is a rare but devastating disease mainly affecting young women, although the increased incidence of PAH among patients with scleroderma and cirrhosis is changing the demographics of the illness. Survival is dismal with untreated advanced patients having a 50% six-month mortality.
The widespread introduction of continuous prostacyclin infusion in 1996 revolutionized treatment for the disease (Barst et al., “A Comparison of Continuous Intravenous Epoprostenol (Prostacyclin) with Conventional Therapy for Primary Pulmonary Hypertension. The Primary Pulmonary Hypertension Study Group,” New Engl. J. Med. 334(5):296-302 (1996)) and has markedly improved survival—60% three year survival with contemporary therapy (Kawut et al., “New Predictors of Outcome in Idiopathic Pulmonary Arterial Hypertension,” Am. J. Cardiol. 95(2):199-203 (2005)).
Unfortunately, there are still only five drugs with regulatory approval for the treatment of this unusual illness (Farber et al., “Pulmonary Arterial Hypertension,” New Engl. J. Med. 351(16):1655-65 (2004); Humbert et al., “Treatment of Pulmonary Arterial Hypertension,” New Engl. J. Med. 351(14):1425-36 (2004)), and many patients progress to lung transplantation or death despite the best available therapy. Even considering the progress made in treating patients, an understanding of the disease process remains limited (Newman et al., “Pulmonary Arterial Hypertension: Future Directions: Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop,” Circulation 109(24):2947-52 (2004)).
In advanced PAH of many etiologies, endothelial proliferation and medial hypertrophy ultimately obliterate the arterial lumen. Most patients also have disordered angiogenesis in glomeruloid-like structures called plexiform lesions (Pietra et al., “Histopathology of Primary Pulmonary Hypertension. A Qualitative and Quantitative Study of Pulmonary Blood Vessels from 58 Patients in the National Heart, Lung, and Blood Institute, Primary Pulmonary Hypertension Registry,” Circulation 80(5):1198-206 (1989); Meyrick, “The Pathology of Pulmonary Artery Hypertension,” Clin. Chest Med. 22(3):393-404 (2001); Tuder et al., “Exuberant Endothelial Cell Growth and Elements of Inflammation are Present in Plexiform Lesions of Pulmonary Hypertension,” Am. J. Pathol. 144(2):275-85 (1994)). Plexiform lesions are not seen in any disease of the systemic arterial circulation. However, these unique structures do share a resemblance with the vessels in a rare form of cancer, glioblastoma multiforme (Tuder et al., “Exuberant Endothelial Cell Growth and Elements of Inflammation are Present in Plexiform Lesions of Pulmonary Hypertension,” Am J Pathol 144(2):275-85 (1994)), and the cells that make up the lesions may be causative in the progression of PAH. There is some data from human autopsy studies to support the hypothesis that plexiform lesions precede the development of concentric luminal obliteration and are therefore critical to the vascular remodeling (Cool et al., “Three-Dimensional Reconstruction of Pulmonary Arteries in Plexiform Pulmonary Hypertension Using Cell-Specific Markers. Evidence for a Dynamic and Heterogeneous Process of Pulmonary Endothelial Cell Growth,” Am. J. Pathol. 155(2):411-9 (1999)). Thus, proliferative vascular lesions and concentric luminal obliteration would be desirable in an animal model of severe PAH to study the mechanisms that mediate this unusual proliferation of vascular endothelial and smooth muscle cells (Newman et al., “Pulmonary Arterial Hypertension: Future Directions: Report of a National Heart, Lung and Blood Institute/Office of Rare Diseases Workshop,” Circulation 109(24):2947-52 (2004); Tuder et al., Exuberant Endothelial Cell Growth and Elements of Inflammation are Present in Plexiform Lesions of Pulmonary Hypertension,” Am. J. Pathol. 144(2):275-85 (1994); Humbert et al., “Cellular and Molecular Pathobiology of Pulmonary Arterial Hypertension,” J. Amer. Coll. Cardiol. 43(12 Suppl S):13S-24S (2004); Rubin et al., “Pulmonary Arterial Hypertension: a Look to the Future,” J. Amer. Coll. Cardiol. 43(12 Suppl S):89S-90S (2004)). Such a model would also be very useful for rational drug development.
The endothelial toxin monocrotaline (“MCT”) is commonly used to produce an experimental model of PAH in which the animals develop a “rugged” appearing endothelium and medial hypertrophy. However, two pathologic hallmarks of human disease, concentric luminal obliteration and plexiform lesions, are not observed. In the rat model pioneered by Botney, MCT is administered to rats following left pneumonectomy. These animals develop more severe PAH with neointimal formation and concentric obliteration in most of the distal pulmonary vessels (Okada et al., “Pulmonary Hemodynamics Modify the Rat Pulmonary Artery Response to Injury. A Neointimal Model of Pulmonary Hypertension,” Am. J. Pathol. 151(4):1019-25 (1997)), much like that seen in human disease. While these models have been useful in defining important pathways of vascular remodeling and thus suggesting novel treatment strategies (Cowan et al., “Elastase and Matrix Metalloproteinase Inhibitors Induce Regression, and Tenascin-C Antisense Prevents Progression, of Vascular Disease,” J. Clin. Invest. 105(1):21-34 (2000); Nishimura et al., “Simvastatin Rescues Rats from Fatal Pulmonary Hypertension by Inducing Apoptosis of Neointimal Smooth Muscle Cells,” Circulation 108(13):1640-5 (2003); Zhao et al., “Rescue of Monocrotaline-Induced Pulmonary Arterial Hypertension Using Bone Marrow-Derived Endothelial-Like Progenitor Cells: Efficacy of Combined Cell and eNOS Gene Therapy in Established Disease,” Circ. Res. 96(4):442-450 (2005)), the absence of some classic pathologic features of human disease is an important limitation for both models. Plexiform lesions have not been reported in these rats or any other animal model of PAH.
It would be desirable, therefore, to develop an animal model of severe PAH that can more accurately reflect the symptoms exhibited by human patients, including both luminal obliteration and formation of plexiform (or plexiform-like) lesions. Such a model, if developed, would be more likely to provide reliable observations for the testing or screening of therapeutic agents that can be used to treat or prevent PAH (or manage symptoms thereof).
The present invention is directed to overcoming these and other deficiencies in the art.